CIinical Geneties 1975: 7 : 426-434

Autosomal recessive syndrome of cerebellar ataxia and hypogonadotropic hypogonadism" GERHARD NEUHAUSERI

AND

JOHNM.

OPITZZ

Visiting Professor, Harry A. Waisnian Center on Mental Retardation and Human Developmentl, Director Wisconsin Clinical Genetics Centerz, and Departments of Pediatrics and Medical Genetics, University of Wisconsin Center for Health Sciences and Medical School, Madison, Wisconsin, U.S.A. An ataxia-hypogonadism syndrome is reported in at least four of 15 family members (two brothers and two sisters). Consanguinity could be proven by genealogical studies; parents were second cousins. The onset of cerebellar ataxia in three sibs was at about 12-20 years, in the proposita at 33-38 years; progression was very slow. Hypogonadotropic hypogonadism was reflected in failure of maturation of secondary sexual characteristics, eunuchoidism, absence of libido and infertility. The concurrence of hereditary ataxia and hypogonadotropic hypogonadism is discussed and explained as pleiotropic effects caused by the homozygous state of a rare autosomal recessive gene. A review of the literature suggests that this is a previously undescribed disorder. Received 4 December, accepted for publication 31 December 1974

T h e classification of hereditary ataxias is still controversial and unsettled. Since underlying metabolic disturbances are not known in any of them, only a combination of clinical, genetic and, under the best of circumstances, neuropathological findings can establish the criteria necessary for a reasonable pathogenetic and etiologic classification (Greenfield 1954, Konigsmark & Weiner 1970, Skre 1972). O n the other hand, some hereditary ataxias are accompanied by non-neurological manifestations, e.g. cardiac involvement, endocrine dys-

function o r skeletal abnormalities (Becker 1966). These are useful for nosologic differentiation of several special types of cerebellar disorders; one of these is the ataxiahypogonadism syndrome (so-called by Rimoin & Schimke 1971). T h e associated manifestations could also give some insight into the pleiotropic action of mendelian genes and m a y be of diagnostic help in linkage studies of autosomal dominant and X-linked forms (Skre & Berg 1974). W e report t h e findings of a family in which at least four members had a syn-

Supported by NIH Grant GM 20130; and a grant from the Brittingham Foundationl. * Contributed, in part, as paper No. 1808 from the University of Wisconsin Genetics Laboratory.

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Fig. 1. Pedigree of the family. Black symbols: affected members; bar over symbol: personally examined: NM: not married; wife of V-14 had 4 spontaneous abortions.

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drome of cerebellar ataxia and hypogonadism, evidently inherited as an autosomal recessive trait. The proposita, who was studied in greater detail, showed hypogonadotropic hypogonadism, a rare condition, particularly if combined with cerebellar ataxia. Clinical Findings

Case I (AK-040914; V-9 in the pedigree, Fig. 1; UW Hosp. No. 453555) This 53-year-old woman was admitted because of slowly progressive difficulties in walking, first described as weakness, beginning between 33-38 years. During the last 2 years she fell more frequently and noticed increasing unsteadiness. She felt “drunk”; her handwriting became very unsteady. Speech had deteriorated during the same time, so that “words do not come out as they should” (“she fumbles her words”). Since childhood the patient had

suffered frontal headaches which recurred every 1-2 months. For the past 5 years she complained of “dizziness, light-headedness, and blurring of vision when she turned her head”. She had come to feel more nervous during the recent past. Family History (Fig. 1) Patient is the ninth of 15 children. The fact that her father and mother were second cousins was confirmed by genealogical studies. Grandparents (111-1, 111-2, 111-4) were born in Southern Russia (near Odessa) as descendants of German Catholics (1-1 and 1-2); the maternal grandmother (111-3) was born in Germany. Both families came to the USA in 1880 and settled in South Dakota. The parents (IV-1 and IV-2) were born in Scrassburg(?)/Russia and married in South Dakota after “Dispensation from the Impediment of Consanguinity” was granted by the Bishop in 1897. Two brothers and one sister (cases 2-4)

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obviously had the same condition. Two other brothers (V-5 and V-14) are reported to be “very tall” (more than 180 cm) but without neurological symptoms; one of these is probably infertile; the other’s wife had four miscarriages and no living children. Three sisters and four brothers are reported to be healthy and together have 37 children and 45 grandchildren who are all healthy and normally developed. The patient’s mother has “visual difficulties”, her father died of a respiratory disorder (? emphysema) and a “weak heart” at 64 years. Neurological symptoms were not noted in the parents or in any other family member. P a tien t’s His tory The early development was apparently normal. After completing 8th grade she worked on a farm. She never menstruated and had no breast development. After an appendectomy in 1942 she was told that her internal genitalia had not developed. She married in 1944 but had no sexual relations with her husband. Other conqh i nts. She feels generally weak and rather fatigued, suffers from dyspnea on exertion as well as some shortness cf breath at rest. She complains of a crawling sensation in her left ear, a flip-flop sensation in the lower chest, epigastric pain and mild dorsal backache. She suffers from chronic constipation. The patient denies changes in thinking or loss of memory over the last few years. Physical Examination

Patient is a thin, tremulous, very anxious woman. Weight 50 kg, height 162.5 cm; upper and lower body segments measured 73.5 crn and 89 cm, respectively (ratio 0.82); the arm span was 168 cm. Pulse was 64/min, and blood pressure 230178 mmHg.

Skin was warm, dry, pale, and of good turgor. Texture of scalp hair was normal; there was some crown baldness and slight frontal recession of the hairline. She had no significant facial hair, minimal axillary hair, sparse pubic hair of female distribution, no breast tissue, no areolar pigmentation. Head shape was normal and head circumference (OFC) was 56.5 cm. The inner canthal distance was 33 mm. There was some flattening of the markings of the auricles, an accessory upper outer crus of the antihelix bilaterally, and minimal torus palatinus. The neck was supple with slight shortening and a normal nuchal hairline; no webbing was evident. The thyroid gland was normal, the thorax relatively broad and heart, lungs and abdomen were apparently normal. She had slight, left convex dorsal scoliosis. The right arm and right leg were about 1 cm shorter than the left; there was slight 5th finger clinodactyly on the left side. Arches on the feet were suggestive of slight pes c a w s bilaterally. Dernzatoglyphics Right palm : proximal triradius ( t ) , no thenar pattern, hypothenar

carpal loop and fourth interdigital distal loop; left palm: t , no thenar, hypothenar, or interdigital pattern; fingertips: whorl on the left index finger and ulnar loops on all other fingers (total ridge count 96). Neurological Examination She had marked vertical nystagmus at rest and horizontal nystagmus on lateral gaze bilaterally. Pupils were normal in shape and reaction, and the discs normal on fundoscopy. Corneal reflexes, facial muscular function, hearing and coughing were normal. There was no evidence of muscle wasting, but some hypotonia of the limbs was evident. There was hyperreflexia, especially in

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the arms (more pronounced on the left than on the right). The plantar responses were flexor and there were no abnormal finger or toe signs. The superficial reflexes were normal and there were no sensory changes. Muscle strength testing elicited some rebound phenomenon on the right side. She showed dishing of hands with slight dyssynergia, occasional dysmetria and moderate intention tremor on finger-nose-test, minimal dysdiadochokinesia, marked ataxia on knee-heel-test, marked intention tremor on toe-object-test, an ataxic, wide based gait, difficulty in heel-to-toe walking with falling, and slight scanning of speech on test phrases. Romberg sign was not present. Special Investigations

Gynecologic examination showed: no breast tissue, immature nipples and external genitalia, tiny clitoris, small vaginal introitus, normal depth and caliber for an unstimulated vagina, small cervix, a tiny uterus, and no adnexal structures on rectal examination. Endocrine studies: PBI: 5.8 pg%, 11"uptake: 15%/24 h (normal thyroid status). 17-ketosteroids: 1.8 mg/24 h, 17-hydroxysteroids 2.6 mg/24 h, FSH less than 5 mouse-uterus-units/24 h. ACTH-stimulation: day 1: 17-KS 11.7, 17-OH-steroids 16.8; day 4: 17 KS 19.2, 17-OH-steroids 32.6 mg/24 h. Other laboratory tests: Urinalysis normal. Free acid on gastric analysis. CBC, FBS normal. 2-h blood sugar, BUN, uric acid, cholesterol, serum-electrolytes, Ca, P, bilirubin, SGOT, LDH, alkaline phosphatase, TSP and albumin, serology and serum bromide levels all normal. Porphobilinogen 0.1 mgil, delta-aminolevulinic acid 2.4 mgil.

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Neurophysiologicd studies: Electroencephalogram normal. T e n d o n - and neo-stigminetest normal. Electromyogram: No evidence of degenerations, no fasciculations. Motor unit potentials of slightly reduced numbers, prolonged duration and increased amplitude in most muscles tested. Normal resting and insertional activity. Signs of minimal diffuse neurogenic atrophy of lower extremities, distally more than proximally. No evidence of myasthenia gravis. Nerve conduction normal for age (54.8 m/s at peroneal nerve). Eye exurnination: Vertical nystagmus. Early senile macular degeneration, manifested by some pigmentary changes. No signs of optic atrophy. Radiological studies: Brain-scan normal, skull and chest roentgenograms normal. No platybasia was found but a left-convex middorsal scoliosis and some flattening of the vertebrae involved in the scoliosis, mild degenerative changes of the dorsolumbar spine, and congenital fusion of D11 and D12. Electrocardiogram was normal. Neuropsychological testing: Tests of biological intelligence yielded an impairment index of 7 indicating mild to moderate impairment of abilities dependent upon organic brain function. Wechsler-AIS showed a VIQ of 74 and PIQ of 82 (full scale IQ 76, low normal range). On tests of cognitive and adaptive abilities the patient demonstrated impairment in most measures, but memory functions and results of tests of sustained auditory attention were within normal limits. The motor examination revealed a relative finger oscillation deficit in the right upper extremity. The Tactual Performance Test was slow bilaterally. The Dynamometer Test yielded essentially nor-

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ma1 grip strength and a normal relationship between the hands. The Motor Steadiness Battery revealed a marked deficit in kinetic coordination which appeared to be slightly more pronounced in the left than in the right body side. Measures of static steadiness appeared to be within normal limits; however, there was a moderate resting steadiness bilaterally, aiid results of the Grooved Peg-board Test revealed rathcr pronounced disability in fine manipulative skills clearly greater for the right than the left hand. The sensory examination failed to show evidence of tactile, auditory, or visual imperception. There was no finger agnosia or significant impairment of fingertip number writing perception. Roughness discrimination was impaired bilaterally, but more pronounced for the right than the left side. There was no definite dysstereognosis. The MMPT yielded a generally elevated scale with a peak on the paranoia scale. Summary: Evidence of essentially undifferentiated bilateral intellectual impairment associated with a rather marked deficit in kinetic coordination tasks. Case 2 (PW-220799; V-2 in pedigree) This older sister of the proposita died in 1964 at 65 years. It was reported that she had no breast development and had never menstruated. Slowly progressive ataxia and tremor began at about 12 years. She was married but childless. At 63 years she became blind. The following medical information could be obtained about her (based on an examination by Dr. E. C . Grubbs, Lemon Grove, California in 1962): Retinal atrophy (probably due to retinal chorioretinitis) was the presumed cause of her blindness. Chest roentgenograms showed pulmonary emphysema with interstitial fibrosis. Diastolic hypertension with blood pressure values between 160/115 and 165/110 mmHg was noted. An upper motor neuron disease of the lower extremities was probably due

to prior stroke; gait ataxia was present. Underdevelopment of female organs (? ovarian dysgenesis) had already been diagnosed earlier; a supracervical hysterectomy and oophorectomy had been performed. Because of diverticulitis the lower descending and sigmoid colon were removed in 1963. Thereafter gradual deterioration occurred; the patient died of “heart weakness”; an autopsy was not performed. Case 3 (BR-200110; V-7 in pedigree) This older brother of the proposita was not married. Gait disturbances began at 12 years and progressed very slowly. Physical examination at 58 years showed a eunuchoid body habitus, a height of 181.5 cm; upper body segment 80 cm, lower body segment 101.5 cm with an UBS/LBS ratio of 0.78; the span was 203 cm. He had soft, wrinkled, eunuchoid skin, gynecomastia, minimal pubic hair with female distribution, small, firm testes (1.5 x 2 X 0.5 cm); large ears, hypoplasia of upper outer crus of antihelix with large fossa triangularis, apparent hypertelorism with an inner canthal distance of 34 mm, intermediate-pitch voice, a neurological syndrome like that of his sister with intention tremor, gait ataxia, and weakness. He was shy, self-conscious, had a childish affect, good memory, and minimal or no mental retardation. Case 4 (LR-231223; V-15 in pedigree) This youngest brother could not be examined. Since 12-13 years he is reported to have ataxia, tremor, and weakness. He is more than 180 cm tall and has no visual problems. He is married but has no children.

Discusslon

Two sisters and two brothers, four of 15 sibs in the family reported here, show an almost identical syndrome of cerebellar

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ataxia and hypogonadism. Cerebellar symptoms, weakness, gait disturbances and tremor occurred first at about 12-20 years in three of the sibs, at 33-38 years in the proposita. The neurological symptoms of truncal ataxia, nystagmus, muscular hypotonia, rebound phenomenon, dysdiadochokinesia, and speech difficulties are consistent with the diagnosis of cerebellar ataxia. There was no evidence of spinal involvement; minimal signs of peripheral neuropathy were found by electromyography in one patient. In all affected sibs the sexual development was delayed, too. Hypogonadotropic hypogonadism was demonstrated in the proposita; in her sister underdevelopment of internal genitalia was shown by laparatomy. One brother, examined by us, showed obvious eunuchoidism which was also reported in another brother. Both men were infertile; this probably is true of two other brothers of the family. The ataxia-hypogonadism syndrome found in this family is inherited as an autosomal recessive trait. Consanguinity could be proven by genealogical studies; the parents are second cousins (Fig. 1). The type of ataxia occurring in this family is difficult to classify. The clinical picture resembles ( I ) the Pierre Marie type of cerebellar ataxia (which, however, is inherited as an autosomal dominant trait in most cases; Sjogren 1943); (2) the Holmes type of cerebellar ataxia (late cortical cerebellar atrophy, Greenfield 1954, which can be recessively inherited but which has a later age of onset); and (3) the type 11, recessive cerebellar atrophy of Weiner & Konigsmark’s classification (1971) which also has a later onset. The difficulties of classifying hereditary ataxias from the clinical and genetic point of view cannot be discussed here in detail (see Konigsmark & Weiner 1970, Konigsmark & Lipton 1971, Weiner & Konigsmark 1971, Skre 1972). The ataxia-hypo-

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gonadism syndrome reported here probably shows somewhat different ataxic features and is not really comparable with other forms of hereditary ataxias. However, the evaluation of this problem has to be based on further observations of this syndrome, since the manifestation of cerebellar ataxia can vary markedly within one family; this is true for most hereditary ataxias (Greenfield 1954), including Friedreich’s ataxia (Sjogren 1943). It is not uncommon to find endocrine dysfunction in patients with hereditary ataxias. The older literature contains remarks on “disturbances of menstruation”, “delayed menarche”, and “infantilism” (Jendrassik 1911, Strumpell 1918, Speer 1920, Hallervorden 1936, Klein 19371, especially in descriptions of Friedreich’s spino-cerebellar ataxia, which shows an autosomal recessive inheritance in most cases (SjZgren 1943). In his classical paper on “a form of familial degeneration of the cerebellum” Holmes (1907) reports three brothers and one sister who, apart from cerebellar symptoms (age of onset 37-38 years) showed distinct clinical signs of hypogenitalism. Leers & Schulz (1939) analyzed 471 cases of Friedreich’s ataxia and 98 cases of Pierre Marie ataxia; they found hypogenitalism or infantilism in 1.7 and 4.46% of the former, in 1.06 and 5.0% of the latter group. Using correlation statistics they concluded that there is a marked correlation between these gonadal/genital developmental disorders and the hereditary ataxias. In Friedreich’s ataxia a combination of neurological symptoms with other endocrine dysfunction can be seen (e.g. diabetes mellitus). Other organs can be involved, too, such as the cardiovascular system (cardiomyopathy; Becker 1966, Exss et al. 1974) or the skeletal system (Curtius et al. 1935, Leers & Schulz 1939, Tyrer & Sutherland 1961). Some of these manifestations may be secondary effects of the disease; others,

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however, are obviously correlatcd symptoms. Some hereditary ataxias are accompanied by additional neurological deficits such as deafness and optic atrophy (Sylvester 1958), deafness, mental retardation and retinitis pigmentosa (Hallgren 1958), hearing loss, mental retardation, signs of upper and lower motor neuron disease (Berman et al. 1973), extrapyramidal symptoms (Wadia & Swami 1971), or involverncnt of the lower motor neuron (Gianelli et al. 1965). Muscular atrophy (due to peripheral neuropathy) can be shown clinically or electromyographically in many cases (Sjogren 1943, Becker 1966); the delineation of the Roussy-LBvy syndrome can be difficult in such patients. Richards & Rundle (1959) reported a family in which five siblings had been affected by deaf-mutism, mental deficiency, spino-cerebellar ataxia, hypogonadism, and other endocrine abnormalities (low urinary estrogen, low pregnandiol and pregnanetriol, low urinary neutral 17-ketosteroids). Pathological studies of an affected male and female member of this family by Sylvester (1972) showed changes similar to those found in the Roussy-LCvy syndrome together with degeneration of the spiral-ganglion cells; gonadal dysgenesis was present in both cases. Inheritance of this condition (the Richards-Rundle syndrome) seems to be as an autosomal recessive trait. The data of a highly inbred family with cerebellar ataxia and tyrosinase-negative albinism suggested to Skre & Berg (1974) that this combination was due to genetic linkage; however, this could not be proven with certainty. Cutaneous manifestations and ataxia are seen in ataxia telangiectasia, the Refsum syndrome and the ChediakHigashi-Steinbrinck syndrome. Hammel (1958) and Vignalou et al. (1959) reviewed 42 cases with the combination of eunuchoidism and hereditary ataxia. However, the exact type of hypogonadism is not known in

all of these patients, since not all of them had studies of urinary gonadotropins. In some cases of the Klinefelter syndrome with ataxia (Hecht 8: Ruskin 1960, Indemini & Altmann 1961, 1963) chance concurrence of a mendelian gene together with a chromosomal abnormality may be responsible for the clinical picture. However, it is possible that a type of ataxia may be a rare component manifestation of the Klinefelter syndrome. Most reported families (Bernard-Weil & Endtz 1962, Volpe et al. 1963, Matthews & Rundle 1964) suggest that hypogonadism with ataxia is an autosomal dominant trait with male sex limitation or an X-linked recessive trait. In reviewing the literature, Becker (1966) and Lenz (1964) mention only male patients having an ataxia-hypogonadism syndrome. We also have been able to find only few reports in which females show the combination of ataxia and hypogonadism. Kapuscinski (1934) mentions two brothers and one sister with Friedreich’s ataxia, hypogonadism, mental deficiency, and choroidal sclerois. Altschul & Kotlowski (1956) describe the occurrence of ataxia (pallido-cerebello-olivary degeneration), hypogenitalism, choreo-athetosis, and mental deterioration in two sisters and one brother of a family in which a paternal uncle is reported to have a quite similar disease. Boucher & Gibberd (1969) examined two sisters with ataxia, hypogonadotropic hypogonadism and severe retinal degeneration; they thought that a pituitary lesion rather than a gonadal abnormality was responsible for the hypogonadism. None of these conditions are like that of the family reported here. Hypogonadotropic hypogonadism (presumed selective gonadotropin deficiency) has been observed in several sibships in which males and females are affected (Lenz 1964, Rimoin & Schimke 1971); autosomal recessive inheritance is probable in most

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cases, but X-linked recessive and autosomal sex-limited dominant inheritance a r e also discussed. Hypogonadism has been described as a manifestation of a number of genetic syndromes and diseases (Rimoin & Schimke 1971, Bardin 1971). Stewart (1959) discusses the nosologic relationship of t h e condition of two brothers with ataxia, hypogonadism, and “dysraphic signs” t o the Laurence-Moon-Biedl-Bardet syndrome in which a cerebellar defect has also been reported (Van Bogaert & Hariga 1961). Hypogonadism can also be seen in ataxia telangiectasia, the Rud syndrome, the Prader-Willi syndrome, the Zellweger syndrome, the Lowe syndrome, the RubinsteinTaybi syndrome, the von Recklinghausen syndrome o r the Steinert syndrome (see Rimoin & Schimke 1971). Hypogonadism d u e to gonadotropin deficiency could represent hypothalamic dysfunction (Kraus-Ruppert 1958, Mattei et al. 1969), but morphological changes in hypothalamic areas could be shown in only a few cases (Kraus-Ruppert 1958). T h e way in which the neurological disturbances a n d the gonadal dysfunction are related to each other or could affect each other is a n open question (Vague et al. 1960). Extensive studies of endocrine functions in patients with various types of ataxias and other neurological disorders are necessary.

References

Altschul, R. & K. Kotlowski (1956). Pallidocerebello-olivary degeneration with eunuchoidism. J . nerv. nient. Dis. 123, 112116. Bardin, C. W. (1971). Hypogonadotropic hypogonadism in patients with multiple congenital defects. Birth Defects: Original Article Series V11, No. 6 , 175-178. Becker, P. E. (1966). Krankheiten mit hauptsachlicher Beteiligung des spino-zerebellaren ~ j V/1. k , ed. Becker, Systems. ~ u i n u n ~ e / i ~Bd. P. E. Stuttgart, Thieme. Berman, W., R. H. A. Haslam, B. W. Konigsmark, A. J . Capute & C. J . Migeon (1973).

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A new familial syndrome with ataxia, hearing loss, and mental retardation. Arch. Neurol. (Chic.) 29, 258-261. Bernard-Weil, E. & L.-J. Endtz (1962). Sur un cas familial de degeneration spinockrkbelleuse avec eunuchoidisrne hypogonadotrophique. Presse nigd. 70, 524-526. Boucher, B. J. & F. B. Gibberd (1969). Familial ataxia, hypogonadism and retinal degeneration. Acta neurol. scand. 45, 507-510. Curtius, F., F. K. Storring & K. Schonberg (1935). Uber Friedreich’sche Ataxie und Status dysraphicus. Z . ges. Netcrol. Psychiat. 153, 719-743. Exss, R., F. Gulotta, H.C. Kallfelz & M. Volpel (1974). Wernicke’s encephalopathy and cardiomyopathy in a boy with Friedreich’s ataxia. Neuropiidiatrie 5, 162-174. Gianelli, A., A. Serra & M. Bacciagaluppi (1965). An atypical hereditary spinocerebellar syndrome. Acta neurol. scand. 41, 387412. Greenfield, J. G. (1954). The Spino-Cerebellar Degenerations. Springfield, Ill., Charles C Thomas. Hallervorden, J. (1936). Die hereditare Ataxie. Handhuch der Neurologie, Bd. XVI, ed. Bumke-Foerster. Berlin, Springer. Hallgren, B. (1958). Retinitis pigmentosa in combination with congenital deafness and vestibulocerebellar ataxia; with psychiatric abnormality in some cases. A clinical and genetic study. Acta genet. (Basel) 8, 97-104. Hamniel, A. C. (1958). Contribution B I’etude de l’hypogonadisme hypogonadotrophique. These de Paris. Hecht, A. & H. Ruskin (1960). Seminiferous tubule dysgenesis (Klinefelter’s syndrome) associated with familial cerebellar ataxia. J . clin. Endocr. 20, 1184-1190. Holmes, G. (1907). A form of familial degeneration of the cerebellum. Bruin 30, 466-489. Indemini, M. & F. Ammann (1961). HCrCdodegtnerescence spino-cCrCbelleuse (HDSC) . associCe au syndrome de Klinefelter. .IC6nPt. h u m . IQ, 291-325. Indemini, M. & F. Ammann (1963). HCrCdodCgCnCrescence spino-cerebelleuse (HDSC) associte au syndrome de Klinefelter. Confin. neurol. (Basel) 23, 155-164. Jendrassik, E. (191 I). Die hereditaren Krankheiten. Hundbuch der Neurologie, Bd. 11. ed. Lewandowsky, M. Berlin, Springer. Kapuscinski, W. (1934). Uber familiare Aderhautentartung mit ataktischen Storungen. Ber.dtsch.ophthu1.Ge.s. 50, 13.

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Klein, D. (1937). Familienkundliche, korperliche und psychopathologische Untersuchungen iiber eine Friedreich-Familie. Schweiz. Arch. Neurol. Psychiat. 39, 89-1 16, 320-329. Konigsmark, B. W. & L. P. Weiner (1970). T h e olivopontocerebellar atrophies: A review. Medicine 49, 227-241. Konigsmark, B. W. & H. Lipton (1971). Dominant olivopontocerebellar atrophy with dementia and extrapyramidal signs; report of a family through three generations. Birth Defecrs: Original Article Series VII No. 1, 178-191. Kraus-Ruppert, R. (1958). Zur Frage ererbter diencephaler Storungen. (Infantiler Eunuchoidismus sowie Microcephalie bei recessivem Erbgang.) Z . menrchl. Vererb.-u. Konstit.Lehre 34, 643-656. Leers, H. & E. Scholz (1939). Korrelationspathologische Unterauchungen. 2. Die erbliche Ataxie. Z . menschl. Vererb.-u. Konstit.Lehre 22, 703-733. Lenz, W. (1964). Krankheiten des Urogentialsystems. Humangenetik, Bd. I I I A . ed. Becker, P. E. Stuttgart, Thieme. Mattei, A., B. Argemi, J. Paillas & J. Vague (1969). Association de dtgtneration spinocCr6belleuse et d’ impuberisme hypogonadatrophique chez un homme de 28 ans. Ann. M i d . int. (Paris) 120, 583-586. Matthews, W. B. & A. T. Rundle (1964). Familial cerebellar ataxia and hypogonadim. Brain 87, 463-468. Richards, B. W. & A. T. Rundle (1959). A familial hormonal disorder associated with mental deficiency, deaf mutism and ataxia. J . nwnt. Defic. Res. 3, 33-55. Rimoin, D. L. & R. N. Schimke (1971). Genetic Disorders of the Endocrine Glands. St. Louis, Mosby Co. Sj@gren, T. (1943). Klinische und erbbiologische Untersuchungen iiber die Heredoataxien. Actu prychiat. ( K b h . ) Suppl. 27, 1-200. Skre, H. (1972). Hereditary cerebellar affections. Acta neurol. scand. Suppl. 51,265-268. Skre, H . & K. Berg (1974). Cerebellar ataxia and total albinism: a kindred suggesting pleiotropism or linkage. Clin. Genet. 5, 196204. Speer, E. (1920). Vier Geschwister mit Friedreichscher Krankheit. Dtsch. 2. Nervenheilk. 67, 141-150.

Stewart, R. M. (1959). Anomalies of form and function in Friedreich’s ataxia. Scot. med. J . 4, 84-88. Strumpell, A . (1918). Ein 13 jahriger Knabe mit Familiarer Friedreichscher Ataxie. Ber. Med. Ges. Leipzig. Miinch. med. Wschr. 42, 11691170. Sylvester, P. E. (1958). Some unusual findings in a family with Friedreich’s ataxia. Arch. Dis. Childh. 33, 217-221. Sylvester, P. E. (1972). Spino-cerebellar degeneration, hormonal disorder, hypogonadism, deaf mutism and mental deficiency, J . ment. Defic. Res. 16, 203-214. Tyrer, J. H. & J. M. Sutherland (1961). The primary spino-cerebellar atrophies and their asociated defects, with a study of the foot deformity. Brain 84, 289-300. Vague, J., P. Bernard, R. Pache, 1. Coulomb, R. Muratore, C. Delboy & G. Venaud (1960). Les dCgCnCrescences neuro-germinales. Sem. H6p. Paris 36, 1348-1353. Van Bogaert, L. & J. Hariga (1961). La maladie de Bardet-Biedl accompagnke de troubles Ge‘nkt. hum. 10, 347-369. neurologiques. .I. Vignalou, J., P. Berthaux, Ch. Gouygou, J.-F. Colas-Belcour, A. Lemarchal & A. Hammel (1959). Hypogonadisme hypogonadotrophique associ6 B une maladie de Friedreich. Ann. Endocr. (Paris) 20, 172-177. Volpe, R., W. S. Metzler & M. W. Johnston (1963). Familial hypogonadotrophic eunuchoidism with cerebellar ataxia. J . clin. Endocr. 23, 107-1 15. Wadia, N . H . & R.K. Swami (1971). A new form of heredo-familiar spinocerebellar degeneration with slow eye movements (nine families). Brain 94, 359-374. Weiner, L. P. & B. W. Konigsmark (1971). Hereditary diseases of the cerebellar parenchyma. Birth Defects: Original Article Series V l l , NO. 1, 192-196.

Address: G . Neuhiiuser, M . D . J . M . Opitz, M . D. Clinical Genetics Center 109 Genetics Building Madison, Wisc. 53706 U.S.A.